Sub-cellular signaling processes generally involve recognition and transient interactions between biomolecules and switching of conformations. These signaling processes, at times, occur over very long timescales (seconds to minutes). For the on-off signaling to take place at biologically relevant timescales (milliseconds), nature has provided enzymes to catalyze and increase the rates of these processes. One of the major challenges in computational biophysics is describing, at the atomistic detail, biomolecular events that are beyond the microsecond timescale. This project takes advantage of an accelerated molecular dynamics simulation method developed by the principle investigator (PI) to access long timescale events and fully model the enzymatic mechanism of peptidyl prolyl cis-trans isomerases (PPIases). PPIases are a class of ubiquitous enzymes that catalyze the notoriously slow cis-trans switching of the prolyl peptide bond of their protein substrates in many important signaling pathways. The goal of this CAREER project is to investigate the conformational transitions of cis-trans biomolecular switches, including the phosphorylation dependent cis-trans switches, and the associated mechanistic role of PPIases. Experiments have provided wealth of structural insights and kinetic information on PPIases, but they have not been able to provide a complete picture of the mechanism at the atomistic level. Direct observations at this level are hard to achieve with current experimental techniques. As a result, the mechanism of action of PPIases that is required for better understanding of certain sub-cellular processes has been elusive and controversial.
This CAREER project will have broad impacts in fundamental research as well as scientific training. By unraveling the atomistic details of biomolecular switching mechanisms and the accompanying protein dynamics, a better understanding of the inner workings of molecular machines at the physicochemical level will be achieved. And at a higher level, this will undoubtedly illuminate how cellular signaling takes place under normal and aberrant conditions. Also, the knowledge gained from this project will allow the PI to make testable hypotheses and to ask specific questions that can then be addressed experimentally. More importantly, this project provides an excellent opportunity to attract and train the next generation of scientists. Computational chemistry cuts across many disciplines, including chemistry, biology, physics, mathematics, and computer science, and therefore, provides an excellent tool for attracting students into the sciences. An advantage of computational chemistry in teaching is the fact that dynamic atomistic and molecular descriptions of concepts that would otherwise seem abstract can be made understandable. In addition to training undergraduate and graduate students, this project will allow the PI to expose high school students to scientific research in a safe environment and reach out to high school and middle school students through a well-established Bio-Bus outreach program at Georgia State University. This outreach program will help to raise scientific literacy amongst school-aged children and provide access to a larger audience, especially those in school districts with underrepresented minorities in science and engineering.
